Our long-term goal is to obtain the data and knowledge necessary to increase efficiency and reliability in the oral therapy of addiction by optimizing the factors shown to influence intestinal absorption of narcotic analgesics and antagonists. Previous work (ours and others) has provided the basic and necessary data to attack the problems of absorption at the high order of biologic complexity applicable and relevant to the real therapeutic situation. The following conditions will be investigated with respect to their effects on the absorption of methadone, naloxone and cyclazocine: 1) the influence of chronic administration of either methadone, naloxone or cyclazocine on its own absorption; 2) the simultaneous absorption of some dietary constituents namely, inorganic ions (particularly Na ion), sugars and amino acids; 3) the simultaneous movement of water - solvent drag - mimicking the massive daily fluxes of ions and water into and out of the gut; 4) the coadministration of other drugs likely to be used during drug therapy of addiction, including caffeine, ethanol, antihistamines, and oral contraceptive agents; and 5) the effect of acute and chronic administration of the narcotic antagonists on the absorption of methadone. The ability of the model drugs to influence Na ion K ion- ATPase activity or cyclic AMP content will also be investigated. Studies will be carried out in intact animals under conditions as close to physiologic as possible varying only the particular factor under consideration. It is anticipated that this holistic approach to problems of drug absorption will lead us to the generalizations necessary for the realization of our long-term goal. In addition, the knowledge gained in studies of drug transfer across the intestinal epithelium may have application to drug transfer across other biological barriers, such as the blood-brain barrier.